It is now established that insulin-dependent diabetes mellitus (IDDM) is an autoimmune disorder in which the insulin-producing beta cells are specifically destroyed. Overt diabetes is often preceded by the appearance of circulating antibodies specific to insulin (IAAs) [Palmer et al., Science 222: 1337 (1983)]. The nonobese diabetic (NOD) mouse develops IDDM with many similarities to the human disease and is considered to be a good model of type I diabetes [Makino et al., Exp. Anim. 29(1): 1 (1980)]. IAAs have also been found to be present in NOD mice [Reddy et al., Diabetologia 31: 322 (1988); Ziegler et al., Diabetes 38: 358 (1989)], and it has been suggested an immune response to insulin is the rate limiting step in development of diabetes [Eisenbarth et al., J. Autoimmunity 5 (Supplement A): 241 (1992)].
The NOD mouse develops insulin dependent diabetes as a consequence of spontaneous destruction of the insulin-producing pancreatic islet .beta.-cells [Makino et al., Exp. Anim. 29 (1): 1 (1980)] and T cells are the major mediators of this .beta.-cell destruction [Ogawa et al., Biomed. Res. 6(2): 103 (1985); Makino et al., Exp. Anim. 35(4): 495 (1986); Koike et al., Diabetes 36: 539 (1987); Wicker et al., Diabetes 35: 855 (1986); Bendelac et al., J. Exp. Med. 166: 823 (1987); Miller et al., J. Immunol. 140(1): 52 (1988)]. While a number of investigators have isolated and characterized panels of islet-specific T cell clones [Haskins et al., Diabetes 37(10): 1444 (1988); Haskins et al., Proc. Natl. Acad. Sci. U.S.A. 86: 8000 (1989); Nakano et al., J. Exp. Med. 173: 1091 (1991); Reich et al., Nature 341: 326 (1989); Haskins and McDuffie, Science 249: 1433 (1990); Christianson et al., Diabetes 42: 44 (1993); Shimizu et al., J. Immunol. 151: 1723 (1993)], there is little information with regard to the identity of the antigens recognized by these clones. Analysis of a panel of nominally islet-specific T cell lines and clones established from islet-infiltrating lymphocytes obtained from female NOD mice revealed that 22 of 40 (55%) responded to porcine insulin [Wegmann et al., Eur. J. Immunol. 24:1853 (1994)].
Further research of this spontaneously arising T cell response to insulin should provide information on the role of these cells in beta cell damage, epitopes of insulin that are recognized by insulin-specific T cells, and the effect of administration of insulin on the T cell response to insulin.
Studies now show that prophylactic insulin therapy can prevent diabetes in the NOD mouse [Atkinson et al., Diabetes 39:933 (1990); Zhang et al., Proc. Natl. Acad. Sci. U.S.A. 88:10252 (1991)]. Prophylactic insulin therapy is also being used in humans at risk for IDDM [Keller et al., Lancet 341(8850): 927 (1993)].